Referenced in: none

Automatically associated channels: Cav3.1 , SK4

Title: Functional role of the KCa3.1 potassium channel in synovial fibroblasts from rheumatoid arthritis patients.

Authors: Kristin Friebel, Roland Schönherr, Raimund W Kinne, Elke Kunisch

Journal, date & volume: J. Cell. Physiol., 2015 Jul , 230, 1677-88

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25545021

Abstract
Rheumatoid arthritis synovial fibroblasts (RA-SFs) show an aggressive phenotype and support joint inflammation and tissue destruction. New druggable targets in RA-SFs would therefore be of high therapeutic interest. The present study shows that the intermediate-conductance, calcium-activated potassium channel KCa3.1 (KCNN4) is expressed at the mRNA and protein level in RA-SFs, is functionally active, and has a regulatory impact on cell proliferation and secretion of pro-inflammatory and pro-destructive mediators. Whole-cell patch-clamp recordings identified KCa3.1 as the dominant potassium channel in the physiologically relevant membrane voltage range below 0 mV. Stimulation with transforming growth factor β1 (TGF-β1) significantly increased transcription, translation, and channel function of KCa3.1. Inhibition of KCa3.1 by the selective, pore-blocking inhibitor TRAM-34, (and, in part, by siRNA) significantly reduced cell proliferation, as well as expression and secretion of pro-inflammatory factors (IL-6, IL-8, and MCP1) and the tissue-destructive protease MMP3. These effects were observed in non-stimulated and/or TGF-β1-stimulated RA-SFs. Since small molecule-based interference with KCa3.1 is principally well tolerated in clinical settings, further evaluation of channel blockers in models of rheumatoid arthritis may be a promising approach to identify new pharmacological targets and develop new therapeutic strategies for this debilitating disease.